Research

Improvement of immunotherapeutic potential of NK cells through modulation of cystatin F

Code:

J4-1776

Range:

01. July 2019 - 30. June 2022

Range:

0,20 FTE

Leader:

Janko Kos

Field:

4.06 Biotechnical sciences / Biotechnology

Abstract:

The effectiveness of conventional therapeutic modalities, including chemotherapy and radiotherapy, is limited due to drug resistance acquired by tumor cells during systemic treatment. Moreover, convenient antitumor drugs are practically ineffective against cancer stem cells, which represent a dormant pool of cells able to induce tumor recurrence. Cancer immunotherapy may overcome several limitations of conventional treatment regarding triggering drug resistance. Several types of immunotherapy have so far been tested in clinical studies, among them the use of tumor cell-directed monoclonal antibodies, and those acting as immune checkpoint inhibitors achieved the greatest success. Cell-based immunotherapy, which employs the application of autologous or allogeneic tumor specific T cells and NK cells into patients, is less established, however, the results of clinical studies are promising. The advantage of NK cell based immunotherapy in comparison to T cells is that NK cells can lyse tumor cells that are “invisible” to T-cells, including cancer stem cells. They can also promote the transition of tumor stem cells to differentiated tumor cells which are more sensitive for T cells and for conventional treatment. The main obstacle limiting the therapeutic use of NK cells is the loss of their cytotoxicity during the expansion and treatment. This project provides an innovative approach how to improve NK cell cytotoxicity by regulation of cystatin F, which is an important signaling molecule tumor cells utilize to induce immune suppression. Specific properties, such as transcriptional factor, dimeric protein, activation peptidase, glycosylation and transport to endo/lysosomal vesicles, which distinguish cystatin F from other related peptidase inhibitors, guarantee selective targeting of immunosupressive processes in cytotoxic cells with negligible off-target effects. By exploring various methods, developed and applied in this project to impair cystatin F function, such as gene silencing and knock out, inhibition of cystatin F activating peptidase and modulation of glycosylation, we will be able to enhance/prolong the cytotoxicity of NK cells. Long-term cytotoxic NK cells would be more effective for cancer treatment and consequently better outcome for cancer patients is expected.